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WO2010089778A2 - Process for the synthesis of cleistanthin - Google Patents

Process for the synthesis of cleistanthin Download PDF

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Publication number
WO2010089778A2
WO2010089778A2 PCT/IN2010/000066 IN2010000066W WO2010089778A2 WO 2010089778 A2 WO2010089778 A2 WO 2010089778A2 IN 2010000066 W IN2010000066 W IN 2010000066W WO 2010089778 A2 WO2010089778 A2 WO 2010089778A2
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Prior art keywords
formula
compound
prepared
alkali
solvent
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PCT/IN2010/000066
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French (fr)
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WO2010089778A3 (en
Inventor
Om Vir Singh
Sarika Madhusudan Tapadiya
Rahul Ganpat Deshmukh
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Godavari Biorefineries Ltd
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Godavari Biorefineries Ltd
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Priority to EP10738292.1A priority Critical patent/EP2393779B1/en
Priority to US13/147,970 priority patent/US20120029179A1/en
Priority to CN2010800068451A priority patent/CN102307859A/en
Priority to AU2010211991A priority patent/AU2010211991B2/en
Priority to MX2011008295A priority patent/MX2011008295A/en
Priority to BRPI1008117-8A priority patent/BRPI1008117A2/en
Priority to NZ594587A priority patent/NZ594587A/en
Priority to CA2751578A priority patent/CA2751578C/en
Application filed by Godavari Biorefineries Ltd filed Critical Godavari Biorefineries Ltd
Priority to JP2011548848A priority patent/JP2012516886A/en
Publication of WO2010089778A2 publication Critical patent/WO2010089778A2/en
Publication of WO2010089778A3 publication Critical patent/WO2010089778A3/en
Priority to ZA2011/05709A priority patent/ZA201105709B/en
Priority to IL214437A priority patent/IL214437A0/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/02—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
    • C07H9/04—Cyclic acetals

Definitions

  • the present invention relates to a process for preparing a diphyllin glycoside, Cleistanthin, more particularly Cleistanthin A.
  • Diphyllin belongs to the family of lignans.
  • Diphyllin is a phenolic lignan lactone.
  • the lignans are a group of chemical compounds found in plants, particularly in flax seed.
  • Lignans are one of the major classes of phytoestrogens, which are estrogen-like chemicals and also act as antioxidants.
  • Diphyllin exists in the glycosylated form.
  • Cleistanthin is an example of a glycosylated diphyllin.
  • Cleistanthin A is as shown below:
  • glycosylated forms of lignan have been identified for a wide variety of activities. They have been associated with cytotoxic effects as well as antitumor activity and antiinflammatory effects.
  • the conventional process for the isolation of Cleistanthin A from cleistanthus collinus comprises the steps of treating the dried leaves of cleistanthus collinus with petroleum ether to obtain a defatted powder.
  • the defatted powder is extracted with acetone to form a gummy mass, which on further treatment with benzene and chloroform gives a black residue.
  • the spots are obtained on TLC plates, which on chromatogram with heptanes, chloroform and methanol gives Cleistanthin A in the form of blue fluorescent spots.
  • Cleistanthin A is re-crystallized with acetone.
  • WO 2008058897 relates to a V-ATPase or gastric proton pump inhibiting lignan such as diphyllin and related glycosides and derivatives, for use as a medicament in the treatment of excessive osteoclast action or in the treatment of excessive gastric acidification, suitably of the general formula: wherein: R b and R c may together form an alkylene bridge; R d and R e also may together form an alkylene bridge; and each dotted bond independently is present or absent; and wherein the lactone ring is optionally opened and is optionally esterified.
  • the compounds disclosed are of the general formula:
  • An aspect of the present invention encompasses a process to prepare compound of formula I that is Cleistanthin A, wherein the process comprises the steps of reacting compound of formula II with compound of formula III in the presence of a first solvent, a quarternary ammonium salt and a first alkali to form compound of formula IV.
  • the compound of formula IV is further treated with a second solvent and a second alkali to form compound of formula I.
  • the process comprises the steps of reacting compound of formula II with compound of formula III in the presence of a solvent, a quarternary ammonium salt and an alkali to form compound of formula IV.
  • the present invention relates to process for preparing Cleistanthin A and its acetate salt that is Cleistanthin A acetate.
  • An embodiment of the present invention provides a process for preparing compound of formula I that is Cleistanthin A.
  • the reaction scheme of the process is as
  • the process comprises the steps of reacting a compound of formula II with a compound of formula HI in the presence of a first solvent, a quarternary ammonium salt and a first alkali to give a compound of formula IV that is Cleistanthin A acetate.
  • the first solvent used to carry out the reaction is dichloromethane.
  • the quarternary ammonium salt is tetrabutyl ammonium bromide.
  • the first alkali used is sodium hydroxide.
  • Compound of formula IV is further treated with a second alkali in the presence of a second solvent to form compound of formula I that is Cleistanthin A.
  • the reaction mixture is stirred at room temperature for nearly 30 minutes.
  • the second alkali used is potassium carbonate.
  • the second solvent used is methanol.
  • the compound of formula I is (9-(l ,3-Benzodioxol-5-yl)-4-((3,4-di-O-methyI-D- xylopyranosyl)oxy)-6,7-dimethoxynaphtho(2,3-c)furan-l(3H)-one,) that is Cleistanthin A.
  • the compound of formula II is 9-(3', 4'-Methylenedioxyphenyl)-4-hydroxy-6,7- dimethoxynaphtho[2,3-c]furan-l(3H)-one.
  • the compound of formula III is 2-O-Acetyl-3, 4-dimethoxy- ⁇ -D-bromoxylopyranose.
  • the compound of formula IV is (9-(l,3- BenzodioxoI-5-yl)-4-((3,4-di-O-methyl-D-xylopyranosyl)acetate)-6,7- dimethoxynaphtho(2,3-c)furan-l(3H)-one,) that is Cleistanthin A acetate.
  • the process for preparing Cleistanthin A is simple and economically viable with a high yield of 96% of Cleistanthin A.
  • Another embodiment of the present invention relates to a process for preparing compound of formula IV that is Cleistanthin A acetate.
  • the reaction scheme of the process is as follows:
  • the process comprises the steps of reacting a compound of formula II with a compound of formula III in the presence of a solvent, a quarternary ammonium salt and an alkali to give a compound of formula IV that is Cleistanthin A acetate.
  • the solvent used to carry out the reaction is dichloromethane.
  • the quarternary ammonium salt is tetrabutyl ammonium bromide.
  • the alkali used is sodium hydroxide.
  • the compound of formula II is 9-(3', 4'-Methylenedioxyphenyl)-4-hydroxy-6,7- dimethoxynaphtho[2,3-c]furan-l(3H)-one.
  • the compound of formula III is 2-O-Acetyl-3, 4-dimethoxy- ⁇ -D-bromoxylopyranose.
  • the compound of formula IV is that is Cleistanthin A acetate ((9-(l,3-Benzodioxol-5-yl)-4-((3,4-di-O-methyl-D- xylopyranosyl)acetate)-6,7-dimethoxynaphtho(2,3-c)furan-l(3 ⁇ )-one,).
  • a process for preparing compound of formula II is represented as follows:
  • the process comprises the step of halogenating a compound of formula V to give a compound of formula VI.
  • Halogenation is carried out in the presence of bromine and acetic acid. The reaction is carried out at room temperature for 3-5 hours.
  • Compound of formula VI is refluxed with p-ethylene glycol in the presence of p-toluene sulphonic acid to give compound of formula VII.
  • Compound of formula VII is treated with n-butyl lithium in the presence of tetrahydrofuran and piperonal to form compound of formula VIII. The temperature is maintained to -70 to -80°C- for 1-5 hours.
  • Compound of formula VIII is further heated with diethyl acetylenedicarboxylate in the presence of acetic acid and methylene dichloride to give compound of formula IX. The temperature is maintained from 130-150°C for 1-2 hours. Compound of formula IX is further treated with lithium aluminium hydride in the presence of tetrahydrofuran to give compound of formula II. The temperature is maintained to 0 0 C. The reaction time is from 2-3 hours.
  • the compound of formula V is veratraldehyde or 4,5-dimethoxybenzaldehyde.
  • the compound of formula VI is 2-Bromo-4,5-dimethoxybenzaldehyde.
  • the compound of formula VII is 2-(2-Bromo-4,5-dimethoxyphenyl)-l ,3-dioxolane.
  • the compound of formula VIII is (2-(l,3-Dioxolan-2-yl)-4,5-dimethoxyphenyl)(benzo[d][l,3]dioxol-5-yl)- methanol.
  • the compound of formula IX is Diethyl l-(3',4'-methylenedioxyphenyl)-4- hydroxy-6,7-dimethoxy-naphthaIene-2,3-dicarboxylate.
  • the process comprises the step of reacting a compound of formula X with pyridine.
  • Acetic anhydride is added to the mixture to result in compound of formula XI.
  • the temperature of the reaction mixture is maintained at 0°C for 4-6 hours.
  • Compound of formula XI is further treated with dichloromethane.
  • the reaction mixture is cooled to O 0 C.
  • hydrogen bromide in acetic acid is added to form a compound of formula XII.
  • the reaction is carried out for 1-3 hours.
  • Compound of formula XII is treated with 2,6 lutidine, tetrabutyl ammonium bromide, anhydrous dichloromethane and ethanol at room temperature to form a compound of formula XIII.
  • the reaction mixture is cooled to 0°C.
  • hydrogen bromide in acetic acid is added to from compound of formula III.
  • the reaction time is 2-3 hours.
  • the compound of formula X is D-xylose.
  • the compound of formula XI is Tetra-O- acetyl-D-xylopyranose.
  • the compound of formula XII is 2,3,4-Tri-O-acetyl- ⁇ -D- bromoxylopyranose.
  • the compound of formula XIII is 3,4-Di-O-acetyl-l,2-O-(l- ethoxyethylidene)-D-xylopyranose.
  • the compound of formula XIV is l,2-O-(l- Ethoxyethylidene)-3,4-dimethoxy-D-xylopyranose.
  • the compound of formula XV is 1,2- Di-O-acetyl-3,4-dimethoxy-D-xylopyranose.
  • Cleistanthin A is used to treat diseases such as cancer, excessive gastric acidification, excessive osteoclast action, treatment and prophylaxis of protein kinase C (PKC) related condition in mammals.
  • diseases such as cancer, excessive gastric acidification, excessive osteoclast action, treatment and prophylaxis of protein kinase C (PKC) related condition in mammals.
  • PKC protein kinase C
  • Cleistanthin A was prepared by the following reaction steps:
  • Cleistanthin A acetate was prepared by the following reaction steps:
  • reaction mixture was allowed to cool to room temperature, neutralized by sodium bicarbonate solution and extracted with ethyl acetate (3 x 100 mL). All the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the crude mass was purified by column chromatography over silica gel using ethyl acetate (5- 10%) in hexane as eluent to afford 2-(2-bromo-4,5-dimethoxyphenyl)-l,3-dioxolane (formula VII) as a white solid.
  • reaction mixture was slowly warmed to room temperature and further stirred for 2.5 h. After the consumption of all bromo compound, as confirmed by TLC (50:50, EtOAc: Hexane), reaction mixture was quenched by the addition of saturated ammonium chloride solution and extracted with ethyl acetate (3 x 20 mL). All the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated.
  • reaction mixture was cooled to room temperature, diluted with dichloromethane (10 mL),washed with 5 % sodium bicarbonate solution (3 x 10 mL), organic layer was dried over anhydrous sodium sulfate, filtered and concentrated.
  • the crude reaction mass was purified by flash column chromatography over silica gel using EtOAc:hexane (15:85) to afford diethyl l-(3',4'- methylenedioxyphenyl)-4-hydroxy-6,7-dimethoxynaphthalene-2,3-dicarboxylate (formula IX) as white solid .
  • reaction mixture was poored into cold water (100 mL) and extracted with ether (4 x 100 mL). The organic layers were combined, washed with saturated cupric sulfate solution till the pyridine was removed and then dried over anhydrous sodium sulfate.
  • reaction mixture was diluted with dichloromethane (50 mL), washed with ice water (50 mL) followed by saturated NaHCO 3 solution (50 mL) and finally with brine solution (50 mL). Organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give yellow colored liquid 2-O-Acetyl-3,4- dimethoxy- ⁇ -D-bromoxylopyranose (formula III) as a product.

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Abstract

The present invention relates to a process for preparing compound of formula (I) that is Cleistanthin A. The process comprises the steps of reacting compound of formula (II) with compound of formula (III) in the presence of a first solvent, quarternary ammonium salt and first alkali to form compound of formula (IV). The compound of formula (IV) is further treated with a second solvent and a second alkali to form compound of formula (I). The present invention also relates to the preparation of salt of compound of formula (IV) that is Cleistanthin A acetate.

Description

PROCESS FOR THE SYNTHESIS OF CLEISTANTHIN
FIELD OF THE INVENTION
The present invention relates to a process for preparing a diphyllin glycoside, Cleistanthin, more particularly Cleistanthin A.
DESCRIPTION OF THE BACKGROUND ART
Diphyllin belongs to the family of lignans. Diphyllin is a phenolic lignan lactone. The lignans are a group of chemical compounds found in plants, particularly in flax seed. Lignans are one of the major classes of phytoestrogens, which are estrogen-like chemicals and also act as antioxidants. Diphyllin exists in the glycosylated form. Cleistanthin is an example of a glycosylated diphyllin.
The structure of Cleistanthin A is as shown below:
Figure imgf000002_0001
The glycosylated forms of lignan have been identified for a wide variety of activities. They have been associated with cytotoxic effects as well as antitumor activity and antiinflammatory effects.
The conventional process for the isolation of Cleistanthin A from cleistanthus collinus comprises the steps of treating the dried leaves of cleistanthus collinus with petroleum ether to obtain a defatted powder. The defatted powder is extracted with acetone to form a gummy mass, which on further treatment with benzene and chloroform gives a black residue. The spots are obtained on TLC plates, which on chromatogram with heptanes, chloroform and methanol gives Cleistanthin A in the form of blue fluorescent spots. Cleistanthin A is re-crystallized with acetone.
WO 2008058897 relates to a V-ATPase or gastric proton pump inhibiting lignan such as diphyllin and related glycosides and derivatives, for use as a medicament in the treatment of excessive osteoclast action or in the treatment of excessive gastric acidification, suitably of the general formula: wherein: Rb and Rc may together form an alkylene bridge; Rd and Re also may together form an alkylene bridge; and each dotted bond independently is present or absent; and wherein the lactone ring is optionally opened and is optionally esterified. The compounds disclosed are of the general formula:
Figure imgf000003_0001
SUMMARY OF THE INVENTION
It is an object of the present invention to prepare Cleistanthin A by a synthetic process.
An aspect of the present invention encompasses a process to prepare compound of formula I that is Cleistanthin A, wherein the process comprises the steps of reacting compound of formula II with compound of formula III in the presence of a first solvent, a quarternary ammonium salt and a first alkali to form compound of formula IV. The compound of formula IV is further treated with a second solvent and a second alkali to form compound of formula I. It is an additional aspect of the present invention to provide a process for preparing compound of formula IV that is Cleistanthin A acetate. The process comprises the steps of reacting compound of formula II with compound of formula III in the presence of a solvent, a quarternary ammonium salt and an alkali to form compound of formula IV.
The structures of the compounds are represented below:
Figure imgf000004_0001
Figure imgf000004_0002
Formula II
Figure imgf000004_0003
Formula III
Figure imgf000005_0001
Formula IV
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to process for preparing Cleistanthin A and its acetate salt that is Cleistanthin A acetate.
An embodiment of the present invention provides a process for preparing compound of formula I that is Cleistanthin A. The reaction scheme of the process is as
follows:
Figure imgf000006_0001
The process comprises the steps of reacting a compound of formula II with a compound of formula HI in the presence of a first solvent, a quarternary ammonium salt and a first alkali to give a compound of formula IV that is Cleistanthin A acetate. The first solvent used to carry out the reaction is dichloromethane. The quarternary ammonium salt is tetrabutyl ammonium bromide. The first alkali used is sodium hydroxide. Compound of formula IV is further treated with a second alkali in the presence of a second solvent to form compound of formula I that is Cleistanthin A. The reaction mixture is stirred at room temperature for nearly 30 minutes. The second alkali used is potassium carbonate. The second solvent used is methanol.
The compound of formula I is (9-(l ,3-Benzodioxol-5-yl)-4-((3,4-di-O-methyI-D- xylopyranosyl)oxy)-6,7-dimethoxynaphtho(2,3-c)furan-l(3H)-one,) that is Cleistanthin A. The compound of formula II is 9-(3', 4'-Methylenedioxyphenyl)-4-hydroxy-6,7- dimethoxynaphtho[2,3-c]furan-l(3H)-one. The compound of formula III is 2-O-Acetyl-3, 4-dimethoxy-α-D-bromoxylopyranose. The compound of formula IV is (9-(l,3- BenzodioxoI-5-yl)-4-((3,4-di-O-methyl-D-xylopyranosyl)acetate)-6,7- dimethoxynaphtho(2,3-c)furan-l(3H)-one,) that is Cleistanthin A acetate.
The process for preparing Cleistanthin A is simple and economically viable with a high yield of 96% of Cleistanthin A.
Another embodiment of the present invention relates to a process for preparing compound of formula IV that is Cleistanthin A acetate. The reaction scheme of the process is as follows:
Synthesis of Cleistanthin A acetate (Formula IV)
Figure imgf000007_0001
The process comprises the steps of reacting a compound of formula II with a compound of formula III in the presence of a solvent, a quarternary ammonium salt and an alkali to give a compound of formula IV that is Cleistanthin A acetate. The solvent used to carry out the reaction is dichloromethane. The quarternary ammonium salt is tetrabutyl ammonium bromide. The alkali used is sodium hydroxide.
The compound of formula II is 9-(3', 4'-Methylenedioxyphenyl)-4-hydroxy-6,7- dimethoxynaphtho[2,3-c]furan-l(3H)-one. The compound of formula III is 2-O-Acetyl-3, 4-dimethoxy-α-D-bromoxylopyranose. The compound of formula IV is that is Cleistanthin A acetate ((9-(l,3-Benzodioxol-5-yl)-4-((3,4-di-O-methyl-D- xylopyranosyl)acetate)-6,7-dimethoxynaphtho(2,3-c)furan-l(3Η)-one,). According to another embodiment of the present invention a process for preparing compound of formula II is represented as follows:
Synthesis of Compound of Formula Il
Figure imgf000008_0001
VI VII
Figure imgf000008_0002
The process comprises the step of halogenating a compound of formula V to give a compound of formula VI. Halogenation is carried out in the presence of bromine and acetic acid. The reaction is carried out at room temperature for 3-5 hours. Compound of formula VI is refluxed with p-ethylene glycol in the presence of p-toluene sulphonic acid to give compound of formula VII. Compound of formula VII is treated with n-butyl lithium in the presence of tetrahydrofuran and piperonal to form compound of formula VIII.The temperature is maintained to -70 to -80°C- for 1-5 hours. Compound of formula VIII is further heated with diethyl acetylenedicarboxylate in the presence of acetic acid and methylene dichloride to give compound of formula IX. The temperature is maintained from 130-150°C for 1-2 hours. Compound of formula IX is further treated with lithium aluminium hydride in the presence of tetrahydrofuran to give compound of formula II. The temperature is maintained to 00C. The reaction time is from 2-3 hours. The compound of formula V is veratraldehyde or 4,5-dimethoxybenzaldehyde. The compound of formula VI is 2-Bromo-4,5-dimethoxybenzaldehyde. The compound of formula VII is 2-(2-Bromo-4,5-dimethoxyphenyl)-l ,3-dioxolane. The compound of formula VIII is (2-(l,3-Dioxolan-2-yl)-4,5-dimethoxyphenyl)(benzo[d][l,3]dioxol-5-yl)- methanol. The compound of formula IX is Diethyl l-(3',4'-methylenedioxyphenyl)-4- hydroxy-6,7-dimethoxy-naphthaIene-2,3-dicarboxylate.
According to another embodiment of the present invention a process for preparing compound of formula III is represented as follows:
Synthesis of Compound of Formula IH
Figure imgf000009_0001
X XI XII
Figure imgf000009_0002
Pyridine
X111 XIV XV
Figure imgf000009_0003
The process comprises the step of reacting a compound of formula X with pyridine. Acetic anhydride is added to the mixture to result in compound of formula XI. The temperature of the reaction mixture is maintained at 0°C for 4-6 hours. Compound of formula XI is further treated with dichloromethane. The reaction mixture is cooled to O0C. To this cold solution hydrogen bromide in acetic acid is added to form a compound of formula XII. The reaction is carried out for 1-3 hours. Compound of formula XII is treated with 2,6 lutidine, tetrabutyl ammonium bromide, anhydrous dichloromethane and ethanol at room temperature to form a compound of formula XIII. Compound of formula XIII is treated with methanol and sodium methoxide to obtain a residue. The reaction is carried at room temperature for 1-2 hours. The residue is dissolved in dimethyl formamide and the mixture is cooled to 0 deg C. To the resulting solution sodium hydride is added to form a suspension. Methyl iodide is further added to the resulting suspension to form compound of formula XIV. Compound of formula XIV is dissolved in acetic acid and the reaction mixture is concentrated to obtain a residue. The temperature is maintained at 0°C for 1-2 hours. The residue obtained is further treated with acetic anhydride and pyridine at room temperature to form compound of formula XV. Compound of formula XV is dissolved in dichloromethane. The reaction mixture is cooled to 0°C. To the cooled solution, hydrogen bromide in acetic acid is added to from compound of formula III. The reaction time is 2-3 hours. The compound of formula X is D-xylose. The compound of formula XI is Tetra-O- acetyl-D-xylopyranose. The compound of formula XII is 2,3,4-Tri-O-acetyl-α-D- bromoxylopyranose. The compound of formula XIII is 3,4-Di-O-acetyl-l,2-O-(l- ethoxyethylidene)-D-xylopyranose. The compound of formula XIV is l,2-O-(l- Ethoxyethylidene)-3,4-dimethoxy-D-xylopyranose. The compound of formula XV is 1,2- Di-O-acetyl-3,4-dimethoxy-D-xylopyranose.
Cleistanthin A is used to treat diseases such as cancer, excessive gastric acidification, excessive osteoclast action, treatment and prophylaxis of protein kinase C (PKC) related condition in mammals.
The following example illustrate the invention, but is not limiting thereof.
Example 1: Preparation of Cleistanthin A of Formula I
Cleistanthin A was prepared by the following reaction steps:
/. Synthesis of Cleistanthin A acetate (Formula IV)
To a 50 mL round bottom flask, 9-(3',4'-Methylenedioxyphenyl)-4-hydroxy-6,7- dimethoxynaphtho[2,3-c]furan-l(3H)-one (formula II; 0.30 g, 0.788 mmole), 2-0-Acetyl- 3,4-dimethoxy-α-D-bromoxylopyranose (formula III, 0.446 g, 1.576 mmole) and tetrabutyl ammonium bromide (0.254 g, 0.788 mmole) were taken in dichloromethane (20 mL) with stirring. To this suspension was added 2M NaOH (3 mL) solution and stirring was continued for 2 h at room temperature. After the completion of reaction as judged by TLC (1 :9, EtOAc:DCM), the reaction mixture was extracted with dichloromethane (4 x 20 mL). The combined organic layer washed with 10% NaOH solution (3 x 15 mL) followed by water (2 x 10 mL) and dried over anhydrous sodium sulfate. Inorganic salts were filtered off; filtrate was concentrated under reduced pressure and crude mass which was purified by column chromatography using EtOAc: dichloromethane (04:96) as eluent to Cleistanthin A acetate (formula IV) as white solid.
The yield and NMR details of compound of Cleistanthin A acetate were as follows: Yield: 0.24O g (52%)
1HNMR (CDCl3, 300 MHz): δ = 7.59 (s, IH), 7.04 (s, IH), 6.94 (d, IH, J = 7.8 Hz), 6.81-6.76 (m, 2H), 6.06 (d, IH, J= 13.8 Hz), 6.05 (d, IH, J= 13.8 Hz), 5.47 (d, IH, J = 16.2 Hz), 5.39 (d, IH, J = 14.8 Hz), 5.33 (t, IH, J = 7.2 Hz), 5.10 (d, I H, J - 6.9 Hz), 4.15 (dd, IH, J = 6.0, 13.2 Hz), 4.07 (s, 3H), 3.79 (s, 3H), 3.60 (s, 3H), 3.50 (s, 3H), 3.46- 3.32 (m, 3H), 2.15 (s, 3H). 13CNMR (300 MHz, CDCl3): δ = 169.68, 169.47, 151.83, 150.35, 147.51, 144.05, 135.57, 130.63, 128.37, 126.12, 125.94, 123.57, 1 19.25, 1 10.70, 108.20, 106.10, 101.21, 100.80, 100.58, 81.21**, 81.16**, 77.95, 71.44*, 71.40*, 66.94, 62.77, 59.90, 58.53, 56.22, 55.81, 21.14.
//. Synthesis of Cleistanthin A (Formula I)
To a solution of Cleistanthin A acetate (formula IV, 0.20 g , 0.343 mmole) in methanol (7.5 mL) was added solid anhydrous K2CO3 (0.0925 g .675 mmol) and reaction mixture was stirred at room temperature for 30 min. After completion of reaction as judged by TLC (5:5, EtOAc:Hexane), methanol was removed under reduced pressure, water was added and extracted with CH2Cl2 (2 x 25 mL). Organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to get Cleistanthin A (formula I) as white fluffy solid.
The yield and NMR details of compound of Cleistanthin A were as follows: Yield: 179 mg (96%)
1HNMR (CDCl3, 300 MHz): δ = 7.92 (s, IH), 7.05 (d, IH, J= 1.5 Hz), 6.94 (dd, IH, J = 1.2, 7.8 Hz), 6.83-6.78 (m, 2H), 6.07 (d, IH, J= 14.1 Hz), 6.06 (d, IH5 J= 14.4 Hz), 5.49 (d, 1H, J= 14.7 Hz), 5.42 (d, IH, J= 14.7 Hz), 5.10 (d, IH, J= 5.7 Hz), 4.10 (dd, 1 H, J = 2.4, 12.0 Hz), 4.04 (s, 3H), 3.95-3.88 (m, I H), 3.80 (s, 3H), 3.68 (s, 3H), 3.49 (s, 3H), 3.45 (dd, IH, J = Hz), 3.93-3.30 (m, 3H). 13CNMR (300 MHz, CDCl3): δ = 169.75, 151.77, 150.15, 147.41, 144.09, 135.84, 130.61, 128.90, 128.87, 128.35, 126.79, 123.55, 1 19.13, 1 10.68, 108.10, 106.04, 103.45, 101.16, 101.02, 82.10, 78.20, 71.13*, 71.1 1*, 67.26, 61.13, 60.01, 57.91, 56.15, 55.76.
Signals of rotamers of same carbons due restricted rotation created by glycosidation. Signals of rotamers of same carbons due restricted rotation created by glycosidation Example 2: Preparation of Cleistanthin A acetate of Formula IV
Cleistanthin A acetate was prepared by the following reaction steps:
To a 50 mL round bottom flask, 9-(3',4'-Methylenedioxyphenyl)-4-hydroxy-6,7- dimethoxynaphtho[2,3-c]furan-l(3H)-one (formula II; 0.30 g, 0.788 mmole), 2-0-Acetyl- 3,4-dimethoxy-α-D-bromoxylopyranose (formula III 0.446 g, 1.576 mmole) and tetrabutyl ammonium bromide (0.254 g, 0.788 mmole) were taken in dichloromethane (20 mL) with stirring. To this suspension was added 2M NaOH (3 mL) solution and stirring was continued for 2 h at room temperature. After the completion of reaction as judged by TLC (1 :9, EtOAc:DCM), the reaction mixture was extracted with dichloromethane (4 x 20 mL). The combined organic layer washed with 10% NaOH solution (3 x 15 mL) followed by water (2 x 10 mL) and dried over anhydrous sodium sulfate. Inorganic salts were filtered off; filtrate was concentrated under reduced pressure and crude mass which was purified by column chromatography using EtOAc: dichloromethane (04:96) as eluent to Cleistanthin A acetate (formula IV) as white solid.
The yield and NMR details of compound of Cleistanthin A acetate were as follows: Yield: 0.24O g (52%) 1HNMR (CDCl3, 300 MHz): δ = 7.59 (s, IH), 7.04 (s, IH), 6.94 (d, IH, J = 7.8 Hz), 6.81-6.76 (m, 2H), 6.06 (d, I H, J = 13.8 Hz), 6.05 (d, IH, J = 13.8 Hz), 5.47 (d, IH, J = 16.2 Hz), 5.39 (d, IH, J = 14.8 Hz), 5.33 (t, I H, J = 7.2 Hz), 5.10 (d, IH, J = 6.9 Hz), 4.15 (dd, IH, J = 6.0, 13.2 Hz), 4.07 (s, 3H), 3.79 (s, 3H), 3.60 (s, 3H), 3.50 (s, 3H), 3.46- 3.32 (m, 3H), 2.15 (s, 3H). 13CNMR (300 MHz, CDCl3): δ = 169.68, 169.47, 151.83, 150.35, 147.51, 144.05, 135.57, 130.63, 128.37, 126.12, 125.94, 123.57, 1 19.25, 1 10.70, 108.20, 106.10, 101.21, 100.80, 100.58, 81.21**, 81.16**, 77.95, 71.44*, 71.40*, 66.94, 62.77, 59.90, 58.53, 56.22, 55.81, 21.14.
Signals of rotamers of same carbons due restricted rotation created by glycosidation. * Signals of rotamers of same carbons due restricted rotation created by glycosidation Example 3: Synthesis of 9-(3',4'-Methylenedioxyphenyl)-4-hydroxy-6,7- dimethoxynaphtho[2,3-c]furan-l(3H)- one of Formula II
Compound of formula II was prepared by the following reaction steps:
/. Synthesis of 2-Bromo-4,5-dimethoxybenzaldehyde of formula VI Three necked round bottom flask (500 niL) equipped with dropping funnel, magnetic stirrer, and stopper was charged with veratraldehyde or 4,5-dimethoxybenzaldehyde (formula V, 15 g, 0.090 mole) and acetic acid (210 mL). To this solution was added bromine (9.67 mL) in acetic acid (60 mL) dropwise with constant stirring over half an hour and stirring was further continued for 3 h at room temperature. During this time all the starting materials was consumed as confirmed by TLC (3: 7, EtOAc:Hexane ). Water (250 mL) was added to the reaction mixture and cooled to O0C. The precipitated solid was filtered off, washed with cold water and dried under vacuum to get a white solid 2- bromo-4,5-dimethoxybenzaldehyde (formula VI).
The yield and NMR details of compound of compound of formula VI were as follows: Yield: 19 g (85.85 %)
1HNMR (CDCl3, 300 MHz): δ = 10.19 (s, IH), 7.43 (s, IH), 7.07 (s, IH), 3.97 (s, 3H), 3.93 (s, 3H).
//. Synthesis of 2-(2-Bromo-4,5-dimethoxyphenyl)- 1 ,3-dioxolane of formula VII
Three necked round bottom flask (250 mL) was equipped with Dean-Stark apparatus and reflux condenser, was charged with 2-bromo-4,5-dimethoxybenzaldehyde (formula VI, 19.0 g, 0.07 mole), toluene (200 mL), ethylene glycol (1 1.8 mL, 0.21 mole) and catalytic amount of p-toluene sulphonic acid ( g, mmole). The reaction flask was immersed in oil bath and heated (90-950C) under reflux for 9 h (till all the water removed). After completion of reaction as judged by TLC (2:8, EtOAc: Hexane), reaction mixture was allowed to cool to room temperature, neutralized by sodium bicarbonate solution and extracted with ethyl acetate (3 x 100 mL). All the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude mass was purified by column chromatography over silica gel using ethyl acetate (5- 10%) in hexane as eluent to afford 2-(2-bromo-4,5-dimethoxyphenyl)-l,3-dioxolane (formula VII) as a white solid.
The yield and NMR details of compound of compound of formula VII were as follows: Yield: 19.7 g (88 %)
1HNMR (300 MHz, CDCl3): δ = 7.1 1 (s, IH ), 7.01 (s, IH ), 5.99(s, I H ), 4.18 (t, 2H, J = 6.9 Hz), 4.08 (t, 2H, J= 6.9 Hz), 3.89 (s, 3H), 3.88 (s, 3H).
///. Synthesis of (2-(l ,3-Dioxolan-2-yl)-4,5-dimethoxyphenyl)(benzo[d] [1 ,3]dioxol-5-yl)- methanol of formula VIII
To a flame dried three necked round bottom flask (100 mL) were added 2-(2-bromo-4,5- dimethoxyphenyl)-l,3-dioxolane (formula VII; 1.0 g, 0.0034 mole ) and anhydrous THF (25 mL) under nitrogen atmosphere. The flask was cooling to -78°C in dry ice-acetone bath, «-BuLi (5.3 mL, 0.005 mole) was added dropwise with stirring at -780C and stirred for 15 min. A separate flame dried flask was charged with piperonal (0.517 g, 0.0034 mole) and dry THF (6 mL). The piperonal solution was cannulated to the reaction mixture during 30 min and after the addition; reaction mixture was slowly warmed to room temperature and further stirred for 2.5 h. After the consumption of all bromo compound, as confirmed by TLC (50:50, EtOAc: Hexane), reaction mixture was quenched by the addition of saturated ammonium chloride solution and extracted with ethyl acetate (3 x 20 mL). All the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by tituration with heptane and product (2-(l,3-Dioxolan-2-yl)-4,5- dimethoxyphenyl)(benzo[d][l,3]dioxol-5-yl)-methanol (formula VIII) (4) is sufficiently pure to proceed to next step.
The yield and NMR details of compound of compound of formula VIII were as follows: Yield: 1.00 g (83%) 1HNMR (300 MHz, CDCl3): δ = 7.14 (s, IH), 6.90-6.78 (m, 4H), 6.1 1 (s, IH ), 5.96 (s, 2H ), 5.90 (s, IH), 4.19 (t, 2H, J= 6.6 Hz), 4.16 (t, 2H, J= 6.8 Hz), 4.02 (s, 3H), 3.81 (s, 3H), 3.17 (s, IH ). 13CNMR (300 MHz, CDCl3): δ = 149.42, 148.1 1, 147.57, 146.58, 136.95, 135.43, 126.83, 121.04, 1 19.69, 1 1 1.48, 109.50, 107.92, 107.26, 101.65, 100.93, 71.34, 65.05, 55.94, 55.89.
IV. Synthesis of Diethyl l-(3 ',4 '-methylenedioxyphenyl)-4-hydroxy-6, 7-dimethoxy- naphthalene-2,3-dicarboxylate of formula IX
Sealed tube was charged with (2-(l ,3-dioxolan-2-yl)-4,5- dimethoxyphenyl)(benzo[d][l,3]dioxol-5-yl)methanol (formula VIII, 0.30 g, 0.833 mmole), diethyl acetylinedicarboxylate (0.141 g, 0.833 mole), dichloromethane (0.4 mL) and glacial acetic acid (0.242 mL) and mixure was heated at 140 0C for 1 h. After completion of reaction as judged by TLC (50:50, EtOAc: Hexane ), reaction mixture was cooled to room temperature, diluted with dichloromethane (10 mL),washed with 5 % sodium bicarbonate solution (3 x 10 mL), organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude reaction mass was purified by flash column chromatography over silica gel using EtOAc:hexane (15:85) to afford diethyl l-(3',4'- methylenedioxyphenyl)-4-hydroxy-6,7-dimethoxynaphthalene-2,3-dicarboxylate (formula IX) as white solid .
The yield and NMR details of compound of compound of formula IX were as follows: Yield: 0.29 g (74 %)
1HNMR (300 MHz, CDCl3): δ = 7.73 (s,lH), 6.89 (d, IH, J = 7.8 Hz), 6.81-6.75 (m, 3H), 6.05 (d, 2H, J= 14.4 Hz), 4.44 (q, 2H, J= 7.2 Hz), 4.07 (q, 2H, J =6.9 Hz), 4.05 (s, 3H), 3.77 (s, 3 H), 1.38 (t, 3H, J= 7.2 Hz), 1.08 (t, 3H, J= 6.9 Hz). 13CNMR (300 MHz, CDCl3): δ = 170.30, 168.74, 159.62, 152.37, 149.68, 147.22, 147.06, 132.21, 130.60, 128.99, 127.48, 124.37, 119.81, 1 1 1.42, 107.97, 105.73, 102.76, 101.09, 61.95, 60.81, 56.08, 55.79, 13.87, 13.82.
V. Synthesis of 9-(3 ',4 '-Methylenedioxyphenyl)-4-hydroxy-6, 7-dimethoxynaphtho[2,3- c]furan-l(3H)-one of formula II Two necked round bottom flask (25 mL) was charged with LAH (0.032 g, 0.852 mmol) and anhydrous THF (4 mL) and the mixture was cooled to O0C with stirring. To this suspension, a solution of diethyl l-(3',4'-methylenedioxyphenyl)-4-hydroxy-6,7- dimethoxynaphthalene-2,3-dicarboxylate (formula IX; 0.200 g, 0.426 mmol) in THF (4 mL) was added dropwise at O0C and stirring was continued for 2 h at same temperature. After completion of reaction as judged by TLC (1 :9, MeOH:DCM), reaction mixture was quenched with saturated sodium sulfate solution and extracted with w-butanol (4 x 20 mL). Organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography over silica gel to give yellow solid 9-(3',4'-Methylenedioxyphenyl)-4-hydroxy-6,7- dimethoxynaphtho[2,3-c]furan-l(3H)-one (formula II).
The yield and NMR details of compound of compound of formula II were as follows: Yield: 0.065 (80 %)
1HNMR (300 MHz, DMSOd6) δ = 10.39 (s, IH), 7.61 (s, I H), 7.00 (d, IH, J= 8.1 Hz), 6.94 (s, IH), 6.85 (d, IH, J= 1.5 Hz), 6.75 (dd, IH5 J= 1.5, 8.4 Hz), 6.10 (s, 2H), 5.35 (s, 2H), 3.93 (s, 3H), 3.64 (s, 3H). 13CNMR (300 MHz, DMSOd6): δ = 169.81, 150.66, 149.89, 147.01, 146.76, 145.05, 129.71 , 129.65, 128.95, 123.94, 123.45, 121.85, 1 18.86, 11 1.22, 108.02, 105.63, 101.19, 100.92, 66.71, 55.78, 55.29.
Example 4: Synthesis of 2-O-Acetyl-3,4-dimethoxy-a-D-bromoxylopyranose of Formula III
Compound of formula III was prepared by the following reaction steps:
/. Synthesis ofTetra-O- acetyl-D-xylopyranose of formula XI
To a three neck round bottam flask (500 mL), equipped with guard tube and stopper, were added D-xylose (formula X, 40.0 g, 0.266 mole), pyridine (200 mL) and cooled it at 0 0C. Acetic anhydride (200 mL) was added dropwise to the above mixture at 0 0C. The resulting reaction mixture was stirred at 0 0C for 5 h. After consumption of starting materials, as judged by TLC (5:5, EtOAc:Hexane), reaction mixture was poored into ice water (500 mL) and ether was added (500 L). Organic layer was separated and aqueous layer was extracted with ether (2 x 500 mL). Organic layers were combined and washed with saturated cupric salt solution till free from pyridine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give sticky solid compound Tetra-O- acetyl-D-xylopyranose (formula XI).
The yield and NMR details of compound of compound of formula XI were as follows: Yield: 75 g (89 %) 1HNMR (300 MHz, CDCl3): δ = 6.27 (d, IH, J = 3.6 Hz ), 5.70 (t, IH, J = 9 Hz ), 5.06 (m, 2H), 3.97 (dd, IH, J =6.0, 1 1.1 Hz), 3.72 (t, IH, J = 1 1.0 Hz), 2.18 (s, 3H ), 2.07(s, 6H), 2.03 (s, 3H ).
//. Synthesis of2,3,4-Tri-O-acetyl-a-D-bromoxylopyranose of formula XII 1 L-round bottom flask with guard tube was charged tetra-O- acetyl-D-xylopyranose
(formula XI; 25.0 g, 78.54 mole) and dichloromethane (500 mL) and mixture was cooled to 0 0C in ice bath. To the above cold solution was added hydrogen bromide (33 % in acetic acid; 56 mL) with constant stirring during 1 h and reaction mixture was further stirred at room temperature for 1 h. After completion of reaction as judged by TLC (4:6, EtOAc: Hexane), reaction mixture was washed with ice water (1 x 500 mL), 1 %
NaHCO3 solution (1 x 500 mL), 10 % NaHCO3 solution (2 x 500 mL) and finally by brine solution (1 x 500 mL). Organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtained white solid 2,3,4-Tri-O- acetyl-α-D-bromoxylopyranose (formula XII), which was used directly in the next step.
The yield and NMR details of compound of compound of formula XII were as follows: Yield: 24.0 g (90 %)
1HNMR (300 MHz, CDCl3): δ = 6.59 (d, IH, J= 3.9 Hz), 5.60 (t, I H, J= 9.9 Hz), 5.05- 5.03 (m, IH), 4.77 (dd, IH, J= 3.9, 9.6 Hz), 4.07 (dd, IH, J= 6.3, 1 1.4 Hz), 3.88 (t, IH, J= 1 1.1 Hz), 2.10 (s, 3H), 2.06 (s, 6H ).
///. Synthesis of 3,4-Di-O-acetyl-l ,2-O-(l-ethoxyethylidene)-D-xylopyranose of formula
XIII
Two necked round bottam flask were charged with 2,3,4-Tri-O-acetyl-α-D- bromoxylopyranose (formula XII ; 25.0 g, 73.71 mmole), 2,6-lutidine (1 1.07 mL , 95.82 mmol), tetrabutyl ammonium bromide (9.50 g, 29.48 mmole) and anhydrous dichloromethane (147 mL). To the above mixture was added absolute ethanol (4.7 mL, 81.08 mmole) and reaction mixture was stirred at room temperature under nitrogen atmosphere for overnight. After completion of reaction as judged by TLC (5:5, EtOAc: Hexane), the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using EtOAc: Hexane as eluent to afford 3,4-Di-O-acetyl-l , 2-O-(l-ethoxyethylidene)-D-xylopyranose (formula XIII) as a pale yellow colored liquid.
The yield and NMR details of compound of compound of formula XIII were as follows: Yield: 16.85 g (75 %)
1HNMR (300 MHz, CDCl3): δ = 5.57 (d, IH, J =4.2 Hz), 5.24 (t, IH, J= 3.6 Hz), 4.84- 4.82 (m, IH), 4.20 (t, IH5 J= 1.8 Hz), 3.89 (dd, IH, J= 5.1, 12.3 Hz), 3.71 (dd, IH, J = 6.9, 12.3 Hz), 3.59 (q, 2H, J = 6.9 Hz ), 2.10 (s, 3H), 2.08 (s, 3H), 1.19 (t, 3H, J = 6.9 Hz). IV. Synthesis of l,2-O-(l-Ethoxyethylidene)-3,4-dimethoxy-D-xylopyranose of formula XIV
In a dried round bottam flask (250 mL) was charged with 3,4-Di-0-acetyl-l,2-0-(l- ethoxyethylidene)-D-xylopyranose (formula XIII; 1Og, 32.86 mmole) and anhydrous methanol (157 mL) was added. To the above solution was added catalytic amount of sodium methoxide (300 mg) and stirred at room temperature for 1 h. After the completion of reaction as judged by TLC, reaction mixture was concentrated under reduced pressure and residue was dried under high vacuum. The resulting residue was dissolved in anhydrous DMF (100 mL) and cooled to 00C in ice-bath. To the above cold solution, sodium hydride (3.94 g, 60% dispersion in oil, 164.3 mmole) was added and resulting suspension was with stirring for 1 h. Methyl iodide (12.4 mL, 197.6 mmole) was added dropwise at 0 0C, the reaction mixture was then slowly brought to room temperature during 1 h and further stirred at room temperature for 12 h. After completion of reaction, reaction was quenched by addition of methanol (10 mL), diluted with ethyl acetate (100 mL), washed with water (2 x 50 mL), brine solution (1 x 50 mL) and dried over anhydrous sodium sulfate. The inorganic salts were filtered off, filtrate was concentrated under reduced pressure and residue was purified by column chromatography using EtOAc:hexane (10:90) to afford l,2-O-(l-Ethoxyethylidene)-3,4-dimethoxy-D- . xylopyranose (formula XIV) as a light yellow colored liquid.
The yield and NMR details of compound of compound of formula XIV were as follows: Yield: 6.8g (83 %)
1HNMR (300 MHz, CDCl3): δ = 5.56 (d, IH, J = 4.8 Hz), 4.29-4.26 (m, IH), 3.89 (dd, IH5 J= 3.3, 12.1 Hz ), 3.82-3.69 (m, 5H ), 3.54 (s, 3H ), 3.44 (s, 3H), 3.26 (m, IH), 1.19 (t, 3H, 6.9 Hz).
V. Synthesis of 1 ,2-Di-0-acetyl-3,4-dimethoxy-D-xylopyrcmose of formula XV l,2-0-(l-ethoxyethylidene)-3,4-dimethoxy-D-xylopyranose (formula XIV; 7.5 g, 30.20 mmole) was dissolved in acetic acid (55 mL) and resulting solution was stirred at 0 0C for 1 h. Reaction mixture was concentrated under reduced pressure and the residue was treated with acetic anhydride (26 mL) and pyridine (26 mL). The resulting solution was maintained at room temperature with stirring for overnight. After completion of reaction as judged by TLC (3:7, EtOAc:hexane ), reaction mixture was poored into cold water (100 mL) and extracted with ether (4 x 100 mL). The organic layers were combined, washed with saturated cupric sulfate solution till the pyridine was removed and then dried over anhydrous sodium sulfate. The inorganic solids were filtered off, filtrate was concentrated under reduced pressure and residue was purified by column chromatography over silica gel using EtOAc: hexane (20:80) as eluent to afford l,2-Di-O-acetyl-3,4- dimethoxy-D-xylopyranose (formula XV) as a light yellow colored oil.
The yield and NMR details of compound of compound of formula XV were as follows: Yield: 5.Og (63 %)
1HNMR (300 MHz, CDCl3): δ = 5.62 (d, IH, J= 12 Hz), 4.95 (t, IH J= 7.8 Hz), 4.1 1 (m, IH), 3.57 (s, 3H), 3.48(s, 3H), 3.39-3.31 (m, 3H), 2.10(s, 3H), 2.09(s, 3H).
VI. Synthesis of2-O-Acetyl-3,4-dimethoxy-a-D-bromoxylopyranose of formula III
In a clean and dry 50 mL-round bottam flask, l,2-di-Oacetyl-3,4-dimethoxy-D- xylopyranose (formula XV; 1.0 g, 3.81 mmole) was dissolved in dichloromethane (25 mL) and cooled to OoC in ice bath. To the above cooled solution was added hydrogen bromide in AcOH (33% solution; 2.5 mL) with constant stirring for 1 h and further stirred at room temperature for another 1 h. After completion of reaction as judged by TLC (3:7, EtOAc:Hexane), reaction mixture was diluted with dichloromethane (50 mL), washed with ice water (50 mL) followed by saturated NaHCO3 solution (50 mL) and finally with brine solution (50 mL). Organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give yellow colored liquid 2-O-Acetyl-3,4- dimethoxy-α-D-bromoxylopyranose (formula III) as a product.
The yield and NMR details of compound of compound of formula III were as follows: Yield: 0.98g (90 %)
1HNMR (300 MHz, CDCl3): δ = 6.56 (d, I H, J= 3.9 Hz), 4.56 (dd, IH, J= 3.9, 9.6 Hz), 4.00 (dd, IH, J = 6.3, 1 1.7. Hz), 3.72 (m, IH), 3.56(s, 3H), 3.54 (s, 3H), 3.38 (m, 2H), 2.13 (s, 3H). While the present invention has been described herein with respect to the various exemplary embodiments, it will be apparent to one of the ordinary skill in the art that many modifications, improvements and sub combinations of the various embodiments, adaptations and variations can be made to the invention without departing from the spirit and the scope thereof.

Claims

1. A process for preparing compound of formula I, wherein the process comprises the steps of:
reacting compound of formula II with compound of formula III in the presence of a first solvent, quarternary ammonium salt and first alkali to form compound of formula IV;
treating compound of formula IV with a second alkali and a second solvent to form compound of formula I.
Figure imgf000023_0001
Formula I
Figure imgf000023_0002
Formula II
Figure imgf000023_0003
Formula III
Figure imgf000024_0001
Formula IV
2. The process as claimed in claim 1 wherein the first solvent is dichloromethane.
3. The process as claimed in claim 1 wherein the first alkali is sodium hydroxide.
4. The process as claimed in claim 1 wherein the quarternary ammonium salt is tetrabutyl ammonium bromide.
5. The process as claimed in claim 1 wherein the second alkali is potassium carbonate.
6. The process as claimed in claim 1 wherein the second solvent is methanol.
7. A process for preparing compound of formula IV, wherein the process comprises the steps of: reacting compound of formula II with compound of formula III in the presence of a solvent, quarternary ammonium salt and alkali to form compound of formula IV.
Figure imgf000025_0001
Formula IV
Figure imgf000025_0002
Formula III
Figure imgf000025_0003
Formula II
8. The process as claimed in claim 7 wherein the solvent is dichloromethane.
9. The process as claimed in claim 7 wherein the alkali is sodium hydroxide.
10. The process as claimed in claim 7 wherein the quarternary ammonium salt is tetrabutyl ammonium bromide.
1 1. The process as claimed in claim 1, wherein the compound of formula II is prepared by reducing compound of formula IX in the presence of lithium aluminium hydride and tetrahydrofuran.
Figure imgf000026_0001
12. The process as claimed in claim 11 , wherein the compound of formula IX is prepared by reacting compound of formula VIII with diethyl acetylenedicarboxylate in the presence of acetic acid and methylene dichloride.
Figure imgf000026_0002
13. The process as claimed in claim 12, wherein the compound of formula VIII is prepared by treating compound of formula VII with n-butyl lithium in the presence of tetrahydrofuran and piperonal.
Figure imgf000026_0003
14. The process as claimed in claim 13, wherein the compound of formula VII is prepared by treating compound of formula VI with p-ethylene glycol in the presence of p- toluene sulphonic acid.
Figure imgf000027_0001
Vi VII
15. The process as claimed in claim 14, wherein the compound of formula VI is prepared by treating compound of formula V with bromine in the presence of acetic acid.
Figure imgf000027_0002
v V1
16. The process as claimed in claim 1, wherein the compound of formula III is prepared by reacting compound of formula XV with HBr in acetic acid in the presence of dichloromethane.
Figure imgf000027_0003
17. The process as claimed in claim 16 , wherein the compound of formula XV is prepared by treating compound of formula XIV with acetic acid in the presence of acetic anhydride and pyridine.
Figure imgf000027_0004
XIV XV
18. The process as claimed in claim 17, wherein the compound of formula XIV is prepared by treating compound of formula XIII with methanol and sodium methoxide to form a residue, which is further treated with dimethyl formamide in the presence of sodium hydride and methyl iodide.
Figure imgf000028_0001
XIII XIV
19. The process as claimed in claim 18, wherein the compound of formula XIII is prepared by treating compound of formula XII with 2,6 lutidine, tetrabutyl ammonium bromide, anhydrous dichloromethane and ethanol.
Figure imgf000028_0002
XE XlU
20. The process as claimed in claim 19, wherein the compound of formula XII is prepared by treating compound of formula XI with HBr in acetic acid in the presence of dichloromethane.
A Λ OAC
Figure imgf000028_0003
XI XII 21. The process as claimed in claim 20, wherein the compound of formula XI is prepared by reacting compound of formula X with acetic anhydride in the presence of pyridine.
Figure imgf000028_0004
X XI
PCT/IN2010/000066 2009-02-05 2010-02-04 Process for the synthesis of cleistanthin Ceased WO2010089778A2 (en)

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NZ594587A NZ594587A (en) 2009-02-05 2010-02-04 Process for the synthesis of cleistanthin
CN2010800068451A CN102307859A (en) 2009-02-05 2010-02-04 Process for the synthesis of cleistanthin
AU2010211991A AU2010211991B2 (en) 2009-02-05 2010-02-04 Process for the synthesis of Cleistanthin
MX2011008295A MX2011008295A (en) 2009-02-05 2010-02-04 Process for the synthesis of cleistanthin.
BRPI1008117-8A BRPI1008117A2 (en) 2009-02-05 2010-02-04 Process for the synthesis of cleistanthin
CA2751578A CA2751578C (en) 2009-02-05 2010-02-04 Process for the synthesis of cleistanthin
JP2011548848A JP2012516886A (en) 2009-02-05 2010-02-04 Clay statin manufacturing method
EP10738292.1A EP2393779B1 (en) 2009-02-05 2010-02-04 Process for the synthesis of cleistanthin
US13/147,970 US20120029179A1 (en) 2009-02-05 2010-02-04 Process for the synthesis of cleistanthin
ZA2011/05709A ZA201105709B (en) 2009-02-05 2011-08-03 Process for the synthesis of cleistanthin
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WO2012081039A1 (en) * 2010-12-17 2012-06-21 Godavari Biorefineries Limited Molecules with anticancer activity and uses thereof
CN102516333A (en) * 2011-12-09 2012-06-27 南通大学 Diphyllin1,2-trans-permethoxy glucoside, its preparation method and application thereof
WO2013001352A2 (en) 2011-06-30 2013-01-03 Godavari Biorefineries Limited Synthesis of cleistanthin a an derivatives thereof
JP2016503005A (en) * 2012-12-18 2016-02-01 ゴーダーヴァリ バイオリファイナリーズ リミテッド Drugs for removing tumor progenitor cells
US9650355B2 (en) 2013-01-31 2017-05-16 Korea Institute Of Science And Technology Method for preparation of justicidin a derivatives of arylnaphthalene lignan structure
WO2018193476A3 (en) * 2017-04-20 2019-01-03 Godavari Biorefineries Limited Anticancer compounds

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* Cited by examiner, † Cited by third party
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WO2012081039A1 (en) * 2010-12-17 2012-06-21 Godavari Biorefineries Limited Molecules with anticancer activity and uses thereof
WO2013001352A2 (en) 2011-06-30 2013-01-03 Godavari Biorefineries Limited Synthesis of cleistanthin a an derivatives thereof
US20130012727A1 (en) * 2011-06-30 2013-01-10 Godavari Biorefineries Limited Synthesis of cleistanthin a and derivatives thereof
WO2013001352A3 (en) * 2011-06-30 2013-04-11 Godavari Biorefineries Limited Synthesis of cleistanthin a an derivatives thereof
JP2015501283A (en) * 2011-06-30 2015-01-15 ゴーダーヴァリ バイオリファイナリーズ リミテッド Synthesis of Claystantin A and its derivatives
US8957230B2 (en) 2011-06-30 2015-02-17 Nilesh Shridhar Mulik Synthesis of cleistanthin A and derivatives thereof
AU2012277481B2 (en) * 2011-06-30 2016-10-06 Godavari Biorefineries Limited Synthesis of cleistanthin A an derivatives thereof
CN102516333A (en) * 2011-12-09 2012-06-27 南通大学 Diphyllin1,2-trans-permethoxy glucoside, its preparation method and application thereof
JP2016503005A (en) * 2012-12-18 2016-02-01 ゴーダーヴァリ バイオリファイナリーズ リミテッド Drugs for removing tumor progenitor cells
US9650355B2 (en) 2013-01-31 2017-05-16 Korea Institute Of Science And Technology Method for preparation of justicidin a derivatives of arylnaphthalene lignan structure
WO2018193476A3 (en) * 2017-04-20 2019-01-03 Godavari Biorefineries Limited Anticancer compounds
US11084843B2 (en) 2017-04-20 2021-08-10 Godavari Biorefineries Ltd. Anticancer compounds

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